SUMMARY Multiple Sclerosis (MS) is a debilitating neurological disease affecting almost 2.5 million individuals worldwide. It is known that environmental factors heavily contribute to the etiology of MS, however their roles in disease course are not well understood. One interest in the field is whether or not dietary choices have an impact on disease severity in MS patients. Epidemiological studies have indicated high Body Mass Index (BMI) (?25) as a risk factor for earlier onset of MS, suggesting that high fat diet, which is associated with high BMI, may also be involved, however, their effects on progression of disease severity have not been explored. My proposal investigates the mechanisms linking high BMI and high fat diet to disease course using animal models of MS to test hypotheses generated from preliminary studies in human patients. In collaboration with the MS center at Mt. Sinai, I have analyzed data on brain volume, immune profile and diet in therapy-nave RRMS patients which has revealed several differences between patients with a low BMI (<25) and those with a high BMI (?25), including greater monocytic counts in patients with a high BMI. We have further identified a potential mechanism underlying these differences, specifically, lipid-dependent modulation of DNA methylation in monocytes. Based on these results, my proposal tests the hypothesis that high fat diet leads to an accumulation of plasma ceramides that modify the methylome of genes affecting proliferation and function of monocytes, thereby leading to greater monocytic infiltration, greater CNS damage and more severe disease course using in vitro and in vivo models. The results of this proposal will have a high translational impact by providing essential information on the impact of diet on disease course that can be directly applied to patients.